{"doi":"10.3233/jad-220906","title":"Tryptophan Metabolism and Neurodegeneration: Longitudinal Associations of Kynurenine Pathway Metabolites with Cognitive Performance and Plasma Alzheimer’s Disease and Related Dementias Biomarkers in the Duke Physical Performance Across the LifeSpan Study","abstract":"BACKGROUND: The kynurenine pathway (KP) comprises a family of tryptophan-derived metabolites that some studies have reported are associated with poorer cognitive performance and an increased risk of Alzheimer's disease and related dementias (ADRD). OBJECTIVE: The objective of this study was to determine the associations of plasma KP metabolites (kynurenine [KYN], kynurenic acid [KA], and tryptophan [TRP]) with a panel of plasma ADRD biomarkers (Aβ42/ β40 ratio, pTau-181, glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]) and cognitive performance in a subset of older adults drawn from the Duke Physical Performance Across the LifeSpan (PALS) study. METHODS: The Montreal Cognitive Assessment (MoCA) was used to assess cognitive performance. We used multivariate multiple regression to evaluate associations of the KYN/TRP and KA/KYN ratios with MoCA score and plasma ADRD biomarkers at baseline and over two years (n = 301; Age = 74.8±8.7). RESULTS: Over two years, an increasing KYN/TRP ratio was associated with increasing plasma concentrations of plasma p-Tau181 (β= 6.151; 95% CI [0.29, 12.01]; p = 0.040), GFAP (β= 11.12; 95% CI [1.73, 20.51]; p = 0.020), and NfL (β= 11.13; 95% CI [2.745, 19.52]; p = 0.009), but not MoCA score or the Aβ42/Aβ40 ratio. There were no significant associations of KA/KYN with MoCA score or plasma ADRD biomarkers. CONCLUSION: Our findings provide evidence that greater concentrations of KP metabolites are associated longitudinally over two years with greater biomarker evidence of neurofibrillary tau pathology (pTau-181), neuroinflammation (GFAP), and neurodegeneration (NfL), suggesting that dysregulated KP metabolism may play a role in ADRD pathogenesis.","journal":"Journal of Alzheimer s Disease","year":2022,"id":253972,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9468,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":231464,"name":"William E. Kraus","orcid":"0000-0003-1930-9684","position":1,"is_corresponding":false},{"id":79787,"name":"Heather E. Whitson","orcid":"0000-0002-8417-4846","position":2,"is_corresponding":false},{"id":33062,"name":"Virginia B. Kraus","orcid":"0000-0001-8173-8258","position":3,"is_corresponding":false},{"id":232685,"name":"Patrick J. Smith","orcid":"0000-0002-6374-0298","position":4,"is_corresponding":false},{"id":362880,"name":"Harvey Jay Cohen","orcid":null,"position":5,"is_corresponding":false},{"id":282555,"name":"Carl F. Pieper","orcid":"0000-0003-4809-1725","position":6,"is_corresponding":false},{"id":900476,"name":"Richard A. Faldowski","orcid":"0000-0002-1650-1358","position":7,"is_corresponding":false},{"id":231461,"name":"Katherine S. Hall","orcid":"0000-0002-9834-2011","position":8,"is_corresponding":false},{"id":383772,"name":"Janet L. Huebner","orcid":"0000-0003-1431-1638","position":9,"is_corresponding":false},{"id":88829,"name":"Olga Ilkayeva","orcid":"0000-0002-9779-0883","position":10,"is_corresponding":false},{"id":88787,"name":"James R. Bain","orcid":"0000-0002-8917-9187","position":11,"is_corresponding":false},{"id":63751,"name":"L. Kristin Newby","orcid":"0000-0002-6394-8187","position":12,"is_corresponding":false},{"id":235342,"name":"Kim M. Huffman","orcid":"0000-0003-4708-4734","position":13,"is_corresponding":false},{"id":478456,"name":"Daniel Parker","orcid":"0000-0001-8512-1044","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":null,"created_at":"2026-07-19T00:25:03.918844Z","pmid":"36565121","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}